Phenylacetic acid and aminoalkyl esters thereof



United States Patent (Z-HYDROXYBICY CLO-[2,2,11-HEPTYL 2)PHENYL ACETICACID AND AMINOALKYL ESTERS THEREOF Wilfrid 'Klavehn, Schwetzingen,Germany, assignor to Knoll A.G. Chemische Fabriken, Ludwigshafen(Rhine), Germany, a corporation of Germany No Drawing. Filed Aug. 19,1954, Ser. No. 451,051 Claims priority, application Germany Aug. 28,1953 9 Claims. (Cl. 260-459) The present invention relates to new tropicacid derivatives and more particularly to bicycloalkyl substitutedtropic acid compounds, and to a process of making same.

It is one object of the present invention to provide new and valuableamino alkyl esters of tropic acid derivatives which are characterized bya bicycloalkyl substituent carrying the hydroxyl group of tropic acid.

Another object of the present invention is to provide valuable acidaddition salts of said amino alkyl esters of said tropic acidderivatives.

A further object of the present invention is to provide quaternaryammonium compounds of said amino alkyl esters of said tropic acidderivatives.

Still another object of the present invention is to provide a simple andconvenient process of making such new and valuable amino alkyl esters ofsaid tropic acid derivatives and acid addition salts and quaternaryammonium compounds thereof.

Other objects of the present invention and advantageous features thereofwill become apparent as the description proceeds.

The new derivatives of tropic acid according to the present inventioncorrespond to the following formula wherein R is a saturated orunsaturated bicycloalkanol group having the hydroxyl group at the carbonatom adjacent to the bridge C atom of the bicyclo while R is an aminolower alkyl group the amino group thereof being substituted by loweralkyl groups. Their acid addition salts and the quaternary amoniumcompounds thereof possess surprisingly high spasmolytic properties ofconsiderably prolonged activity. They are of comparatively low toxicityand cause only insignificant side-reactions.

The new compounds are produced according to the process of thisinvention by reacting the organo-metal compounds of salts of phenylacetic acid, for instance, their alkali salts, with saturated orunsaturated bicycloalkanone compounds. Thereby the correspondingbicycloalkanol compounds of phenyl acetic acid are produced. Saidcompounds have the hydroxyl group at the carbon atom of the bicycloalkylring system adjacent to the CH- group of phenyl acetic acid.Subsequently, the resulting bicycloalkanol derivatives of phenyl aceticacid are converted into the corresponding lower alkyl substituted aminolower alkyl esters, for instance, by reacting said bicycloalkanolsubstituted phenyl acetic acid compounds with lower alkyl substitutedamino lower alkyl halogenides. The resulting esters are then convertedeither into their acid addition salts or, by reaction with quaternizingagents, such as alkyl halogenides, dialkyl sulfates, and others, intotheir quaternary ammonium compounds.

2,985,681 Patented May 23, 1961 For instance, the diethylamino ethylester of (2-hydroxy bicyclo(2,2,l)heptyl-2) phenyl acetic acid isobtained by reacting bicyclo(2,2,1)heptanone-2 with the sodium salt ofthe bromo magnesium phenyl acetic acid and converting the resulting freeacid into the corresponding diethylamino ethyl ester. Said ester, ifdesired, is sgilbsequently converted into the quaternary ammonium s t.

Most of the amino alkyl esters of bicyclically substituted tropic acidsare liquid substances which, however, can readily be recovered andisolated from the reaction mixture in the form of their readilycrystallizing addition salts with inorganic or organic acids. When usingsuch acid addition salts for therapeutical purposes, of course, onlysuch acids are combined with said esters which are compatible to thehuman system and do not produce toxic effects. Suitable for suchpurposes are the hydrochlorides, and salts with hydrobromic, sulfuric,phosphoric, nitric, citric, tartaric, malic, maleic, malonic, succinic,benzoic, salicylic, mandelic, p-amino salicyclic, phthalic, isonicotinicacid, penicillin in its acid form, and others may also be produced andemployed for therapeutic purposes.

The quaternary amomnium compounds of bicyclically substituted tropicacids according to the present invention are also, in most instances,water soluble and readily crystallizing compounds.

The following examples serve to illustrate the present inventionwithout, however, limiting the same thereto.

EXAMPLE 1 (Z-hydroxy bicycIo(2,2,I)heptyl-2) phenyl acetic acid (I) 79.6g. of finely pulverized dry sodium salt of phenyl acetic acid areintroduced while strongly cooling, within 2 hours, into an etherealsolution of isopropyl magnesium bromide whereby the organo-magnesiumcompound of phenyl acetic acid is formed. During said reaction propaneis developed. The ethereal isopropyl magnesium bromide solution isprepared by reacting 21.0 g. of magnesium shavings with 111 g. of2-bromo propane in 700 cc. of dry ether.

55.0 g. of bicyclo(2,2,l)heptanone-2(C H O) in 450 cc. of dry ether areadded-drop by drop to said organomagnesium compound of the sodium saltphenyl acetic acid. The reaction is completed by heating under reflux.The reaction mixture is treated with dilute hydrochloric acid in thecold, the ethereal layer is separated and the free acid is removedtherefrom by means of dilute sodium hydroxide solution. Addition ofdilute hydrochloric acid to the aqueous solution of the sodium saltprecipitates the bicyclically substituted phenyl acetic acid in the formof a viscous oil which completely solidifies after some time. The acid CH O of the above given Formula I crystallizes from a mixture of acetoneand ether (2:1) in needles arranged in clusters which melt at 170 C. Theyield is 65% to of the theoretical yield.

3 (Z-hydroxy bicyclo(2,2,1)heptyl-2) phenyl acetic acid diethylaminaethyl ester hydrochloride (II) and (Z-hydroxy bicyclo(2,2,1)heptyl-2)phenyl acetic acid diethyl methyl ammonium' ethyl ester methosulfate(III) 123 g. of the acid C H O are introduced into a solution of 11.5 g.of metallic sodium in 400 cc. of propanol-2. 86 g. of diethylamino ethylchloride hydrochloride in 400 cc. of propanol-Z are added thereto. Themixture is boiled under reflux for 36 hours. After the sodium chlorideformed is removed, the solution is concentrated by evaporation on awater bath under reduced pressure. The residue is treated with dry etheryielding thereby the hydrochloride of the diethylamino ethyl ester ofthe above given Formula II (C H O N.HCl). Said hydrochloridecrystallizes from ethyl acetate in slightly bygroscopic elongatedneedles melting at 132.5 C. The yield is 75% of the theoretical yield.

To convert said tertiary base into the methosulfate, 34.5 g. of the freebase, obtained by carefully neutralizing an aqueous solution of itshydrochloride with sodiumbicarbonate solution and extracting the freebase with ether, are dissolved in 250 cc. of dry ether. 15.1 g. ofdimethylsulfate are added to said solution. After standing for sometime, the quaternary ammonium salt of the above given Formula IIIprecipitates almost quantitatively in solid form. It is readily solublein water, methanol,

and acetone, slightly soluble in ethyl acetate, and insoluble in ether.On recrystallization from a mixture of methyl acetate and ethyl acetate1:1) it is obtained in massive druses melting at 1l4.5 C.

A small amount of a modification of said salt is obtained whichmodification crystallizes from a mixture of ethanol and ethyl acetate inhexagonal leaflets of the melting point 133 C. Total yield: 85% to 90%of the theoretical yield.

Reacting the free base of Formula II with methyl bromide, in place ofdimethyl sulfate, and otherwise proceeding in the same manner asdescribed hereinabove, yields the corresponding 2-(hydroxybicyclo(2,2,1)heptyl- 2) phenyl acetic acid diethyl methyl ammoniumethyl ester bromide.

EXAMPLE 2 79.6 g. of the sodium salt of phenyl acetic acid are convertedas described in Example 1 into the corresponding organo-magnesiumcompound. Said compound is reacted with 54 g. of A-bicyclo(2,2,1)heptenone-Z 5 (C- H O) in 450 cc. of ether. The reactionmixture is worked up as described in Example 1. The unsaturated acid C HO of the above given Formula IV is obtained. Said acid, onrecrystallization from a mixture of acetone and petroleum ether (2:1),crystallizes in the form of long prisms melting at 148.5 C. Yield: 20%to 30% of the theoretical yield.

(2-hydroxyl-A -bicyclo(2,2,1)heptenyl-Z) phenyl acetic acid diethylaminoethyl ester hydrochloride (V) and (2-hydroxy-A-bicyclo(2,2,1)heptenyl-Z) phenyl acetic acid diethyl methyl ammoniumethyl ester bromide or methosulfate (VI), respectively -oH-co0-cm-orr,1s.HC]

-OH 01H: of, on C a l C CH C and /C2Hs -oH-o0oomcm1v c,m

JJQH CH: so CH 0g CH a H C W 122 g. of the free acid C H O areintroduced according to Example 1 into a solution of 11.5 g. of metallicsodium in 400 cc. of propanol-Z. Said solution is boiled under refluxwith 86 g. of diethylamino ethylchloride hydrochloride in 400 cc. ofpropanol-Z for 36 hours. The reaction mixture is then worked upaccording to the procedure described in Example 1. The resultinghydrochloride of the diethylamino ethyl ester C H O N.HCl of the abovegiven Formula V is a slightly hygroscopic salt which crystallizes fromethyl acetate in prisms melting at 103 C. Yield: 60% to 70% of thetheoretical yield.

The methobromide of the quaternary ammonium compound C H O NBr, whichmelts at 130.5" C., is obtained by addition of 9.5 g. of methyl bromideto 38.0 g. of the tertiary base in ethereal solution. It is readilysoluble in water and methanol, slightly soluble in acetone, andinsoluble in ether. Yield: 90% of the theoretical yield.

The methosulfate c H o-ms of the above given Formula VI is obtained in asimilar manner from the tertiary base with dimethyl sulfate. Itcrystallizes from a mixture of acetone and ether (2:1) in small leafletsof the melting point 120-12l C. Yield: 85% to 95% of the theoreticalyield.

EXAMPLE 3 65 (2-hydroxy bicyclo(2,2,1)heptyl-2) phenyl acetic aciddimothylamino ethyl ester hydrochloride (VII) 74 g. of (Z-hydroxybicyclo(2,2,1)heptyl-2) phenyl acetic acid c n o obtained according toExample 1 are dissolved in 240 cc. of propanol-2. Said solution is addedto a solution of 6.9 g. of metallic sodium in 240 cc. of propanol-2.43.2 g. of dimethylamino ethylchloride hydrochloride are added theretoand the mixture is boiled under reflux for 36 hours. The reactionmixture is worked up in a similar manner as described in Example 1,yielding the hydrochloride of the corresponding dimethylamino ethylester C H O N.HCl of the above given Formula VII. On recrystallizationfrom a mixture of methanol and ether (1:1) said hydrochloride isobtained in the form of crystals melting at 143 C. Yield: About 70% ofthe theoretical yield.

The tertiary base prepared from said hydrochloride is reacted with therequired amount of dimethyl sulfate in ethereal solution and yields thequaternary ammonium methosulfate C H O NS which, on recrystallizationfrom a mixture of methyl acetate and ethyl acetate (1:1), melts at 145C. Yield: 80% to 85% of the theoretical yield.

EXAMPLE 4 (Z-hydroxy bicycl(2',2,1)heptyl-2) phenyl acetic acid-1,3-diethylamin0 propyl ester hydrochloride (VIII) 80.7 g. of the sodiumsalt of (Z-hydroxy bicyclo(2, 2,1)heptyl-2) phenyl acetic acid arereacted with 56 g. of LEI-diethylamino propylchloride hydrochloride andthe reaction mixture is worked up in a similar manner as described inExample 1. The resulting hydrochloride of 1,3-diethylamino propyl esterC I-I O NHCl of the above given Formula VIII crystallizes from a mixtureof acetone and ether (1:2) in the form of elongated prisms of themelting point lll-l'l3 C. Yield: 75% of the theoretical yield.

(Z-hydroxy bicycl0(2,2,1)heptyl-2) phenyl acetic acid- 1,3-diethylmethyl ammonium propyl ester methosulfate (IX) CzHl -OH CH: c on CH; CH,(1x) The free base C H 0 N prepared from said above mentionedhydrochloride is reacted with dimethyl sulfate in ethereal solution andyields, in a similar manner as described in the preceding examples, thecorresponding methosulfate C H O- NS of the above given Formula IX whichcrystallizes from a mixture of methyl acetate and ethyl acetate intetragonal laminae melting at 103- 105 C. Yield: 80% to 90% of thetheoretical yield.

In place of bicyclo(2,2,l)heptanone-2 and A -bicyclo- (2,2,l)heptenone-2used as bicyclo-alkanones in the preceding examples there may beemployed equimolecular amounts of other bicycloalkanones, such asbicyclo- (2,2,2)octanone.

In place of the sodium salt of phenyl acetic acid used in the productionof the organo-magnesium compounds of said acid, there can be usedequimolecular amounts, of other alkali salts, such as the potassium orlithium salts, or of other salts of said acid, such as the calcium,

.SOiCH barium, magnesium salts thereof. The alkali salts, however, arethe most preferred salts since they more readily react with theorgauo-metal compound than the other salts.

In place of dimethylamino ethyl chloride, diethylamino ethyl chloride,and diethylamino propyl chloride there may be used equimolecular amountsof other lower dialkylamino lower alkylhalogenides, such asdi-isopropylamino ethyl chloride or bromide, di-n-butylamino ethylchloride or bromide, 1,3-dimethylamino propyl halogenides.

As quaternizing agents there may be used, in place of methyl bromide anddimethyl sulfate employed in the preceding examples, methyl iodide,ethyl bromide, diethyl sulfate, p-toluene sulfonic acid alkyl esters,and others.

As stated above the new compounds are highly effective spasmolyticagents. On account of their anticholinergic properties they aresuccessfully used in the treatment of peptic ulcers.

(Z-hydroxy bicyclo (2,2,1)heptyl-2) phenyl acetic acid diethyl methylammonium ethyl ester-methosulfate of Example 1 has been found to be ofparticular therapeutic interest on account of its considerablesuppressing eifect upon gastric secretion and motility. In this respectit has considerable advantages over other agents used for this purposeand especially over the widely administered drugs atropine andmethantheline bromide.

Its toxicity is much lower than that of atropine and is about the sameas that of methantheline bromide Its DL for the white mouse in onsubcutaneous administration 230 mg. per kg. and on intravenousadminisration 17.1 mg. per kg.

Testing said compound for its spasmolytic action upon isolated guineapig intestines according to the method of Magnus (i.e. suppression ofconvulsions caused by administration of 0.02 mgJ-kg. of histamine,0.02mg./kg. of acetylcholine, or 100.0 mg./ kg. of barium chloride)showed that said compound is at least as effective as the most effectivedrug atropine while methantheline bromide is only about one half to twothirds as active as atropine.

Likewise, its antagonism towards acetylcholine and its inhibiting effectupon vagus irritation, determined on cats under chloralose anesthesia bymeasuring the dose required to suppress the reduction in blood pressurecaused by administration of 0.1 /kg. of acetylcholine and subjectingsaid animals to electric irritation, is considerably more pronouncedthan that of other drugs and is approximately the same as that ofatropine.

Its suppressing efiect upon bronchospasms caused by administration of3-5 mg./kg. of pilocarpine to cats in chloralose anesthesia is greaterthan that of any other drug and even that of atropine. Said efiect isalso of considerably prolonged duration.

Its inhibiting power upon gastric secretion and motility of the smallintestines was tested in dogs in dihydromorphinone-sodium isobutyl bromoallyl barbiturate narcosis. 0.005 mg./kg. of carbamyl choline chloridewas subcutaneously administered to said animals in intervals of half anhour. The drug to be tested was intravenously administered in a dose of0.002 mgJK-g. or 0.005 mg./kg., respectively, after the initial stomachacidity and the increase in acidity caused by the first carbamyl cholinechloride injection were determined. The gastric juice was withdrawn fromthe duodenum by means of a catheter in intervals of a quarter of an hourwhereby before each withdrawal 20 cc. of N/ 10 hydrochloric acid wasintroduced into the stomach in order to ensure that a quantity of liquidsufficient for titration can be withdrawn. (2-hydroxy bicyclo(2,2,1)-heptyl-Z) phenyl acetic acid diethyl methyl ammonium ethyl estermethosulfate reduces gastric acidity, which was increased by carbamylcholine chloride administration, to a much greater extent and has a muchlonger acidity reducing elfect than any of the other tested drugs andalso than methantheline bromide.

Compounds according to the present invention and especially saidZ-hydroxy bicyclo (2,2,l)heptyl-2) phenyl acetic acid diethyl methylammonium ethyl ester methosulfate primarily inhibit the stimulatoryefiect of acetylcholine, in nervous transmission, upon nervousexcitation of the nerve terminations of the parasympathetic portion ofthe autonomic nervous system and, thus, has an atropine-like effectwhile its blocking effect upon the ganglionic synapses in any part ofthe sympathetic or parasympathetic nervous system is probably only of asupplementary and supporting nature.

Compounds according to the present invention do not substantially affectthe circulatory system.

The new compounds are therapeutically administered either in the form oftablets, pills, dragees, powders, solutions or other orallyadministrable preparations or they may be subcutaneously orintramuscularly injected in the form of sterile aqueous or salinesolutions. The daily dose in the treatment of peptic ulcer is 30 to 60mg. given orally three times in the form of 1 to 2 tablets containing 10mg. per tablet, or 2.5 mg. dissolved in 1 cc. of saline solution areinjected subcutaneously or intramuscularly to alford relief from pain.After the ulcer is healed, it is advisable to continue a maintenancedosage of about one half of the therapeutic dosage for some time so asto avoid recurrence.

The new compounds are preferably used in their dilute form, thus,allowing better and more economical use to be made thereof.

In the administration of such compounds in capsules as powders, a fineuniform dispersion of the active product throughout said powder isdesirable. Such a fine dispersion can be achieved, for instance, byintimately mixing and milling the compound in a ball mill with a solid,pulverulent extending agent to the desired degree of fineness, or byimpregnating the already milled, finely powdered, solid carrier with amixture of the active compound in water or other suitable solvents, andthen removing the water or solvent.

When preparing tablets, pills, dragees, and the like, and shaped solidpreparations for oral administration, the commonly used diluting agetns,binder, and the like, are employed, such as sugar, lactose, talcum,starch, bolus alba, and as binders, pectin, gelatin, gum arabic, methylcellulose, yeast extract, agar, tragacanth, and others.

The content of active compound in such preparations may vary. It is, ofcourse, of advantage, that the active compound be present in saidpreparations in such an amount that a suitable dosage will be ensured.The unit dose should contain not less than 0.1% of the active compound.The preferred amounts to be employed in tablets and like shaped solidpreparations are between about 2% and about 10% of the weight on theunit. To use greater amounts is, of course, also possible althoughadministration of suitable dosage becomes somewhat cumbersome.

Injectable preparations contain preferably between 0.2% and 0.5% of theactive compound but may, of course, also contain larger amounts.

Many changes and variations in the reaction conditions, the reactioncomponents, the methods of working up and of purifying the reactionproducts, the forms of preparations used in therapy and the like may bemade by those skilled in the art in accordance with the principles setforth herein and in the claims annexed hereto.

I claim: 1. A tropic acid compound selected from the group consisting ofa tropic acid ester of the formula QUE-(lOO-R: i

its acid addition salts, its quaternary methosulfate, and its quaternarylower alko bromide, whereby @crr-ooon wherein R is a member selectedfrom the group consisting of the 2-hydroxy bicyclo(2,2,1)heptyl-2-groupand the 2-hydroxy-A -bicyclo (2,2,1) heptenyl-Z-group, said 2-hydroxybicyclo (2,2,1) heptyl-2- and 2-hydroxy- A -bicyclo (2,2,1)heptenyl-Z-groups having the hydroxyl group at the carbon atom adjacentto the CH-group of said phenyl acetic acid.

3. (Z-hydroxy bicyclo(2,2,1)heptyl-2) phenyl acetic acid diethylaminoethyl ester hydrochloride cm, @on-ooo-cJm-orn-r/ .1101

( ]-OE czHs C a CH l l 4. (Z-hydroxy bicyclo(2,2,l)heptyl-2) phenylacetic acid diethylamino ethyl ester C1115 CHC0OCH:CH:N/

(J-OH clm c OH l C( CH:

5. (2-hydroxy-A -bicyclo(2,2,1)heptenyl-2) phenyl acetic acid diethylmethyl ammonium ethyl ester methosulfate 6. (2-hydroxybicyclo(2,2,1)heptyl-2) phenyl acetic acid diethyl methyl ammonium ethylester methosulfate Gin-c o o-cm-orn-rrcm.

--\OH on; cg on .SOACHI' 9 10 7. (Z-hydroxy bicyclo(2,2,1)hepty1-2)phenyl acetic 9. The (2-hyd1'oxy-A;-bicyclo(2,2,1) heptenyl-Z) phenaclddiethyl methyl ammonium othyl ester bromide yl acetic acid of theformula Q-cn-ooo on on 11 Goa-coon on P 0? 6 i i 06 ;cn I c I l in m i HI c 8. The (Z-hydroxy bicyclo(2,2,l)heptyl-2) phcnyl ace- Mmnc in filetic acid of the formula UNITED STATES PATENTS 15 2,554,511 Treves May29, 1951 2,558,020 Treves June 26, 1951 -OH g FOREIGN PATENTS 4, 100,391Great Britain Dec. 2, 195a H 20 138,953 Sweden Feb. 3, 1953

1. A TROPIC ACID COMPOUND SELECTED FROM THE GROUP CONSISTING OF A TROPICACID ESTER OF THE FORMULA
 2. A SUBSTITUTED PHENYL ACETIC ACID OF THEFORMULA